Yttrium [90Y] microspheres, their preparation method and use

Abstract

This application relates to the technical field of radiopharmaceutical formulations, in particular yttrium [ 90 The present invention relates to polystyrene sulfonate-type resin microspheres, their preparation method, and use. The microspheres contain polystyrene sulfonate-type resin microspheres and yttrium-90 adsorbed within the polystyrene sulfonate-type resin microspheres. By adsorbing yttrium-90 onto the polystyrene sulfonate-type resin microspheres, the adsorption strength is significantly improved, the safety of preparation and use is significantly improved, and the killing effect on tumor cells is also favorable.

Description

[Technical Field]

[0001] This application is filed with the China Patent Office on October 25, 2023, with application number 202311388190.4 and title of invention "Yttrium [ 90 Y] Microspheres, Preparation Methods and Uses Thereof,” the entire contents of which are incorporated herein by reference.

[0002] This application relates to the technical field of radiopharmaceutical formulations, in particular yttrium [ 90 Y] microspheres, their preparation method and use. [Background technology]

[0003] Interventional radiology techniques have been developed in recent years as an effective method for treating tumors, and yttrium [ 90 Y] is attracting attention as a radioactive treatment due to its advantages of high energy, short half-life, short penetration distance in the body, and ease of protection. 90 Y] Microsphere injection precision intervention therapy is a technique that combines intervention with precision internal radiation therapy. Yttrium [ 90 [Y] Radioactive microspheres, as an important therapeutic tool for liver cancer treatment, are expected to provide a powerful weapon for the comprehensive treatment of liver cancer patients in China, which can increase the cure rate and prolong overall survival.

[0004] Yttrium-90 glass microspheres and styrene-divinylbenzene copolymer microspheres have been used to treat liver cancer, but these microspheres have the disadvantage of not being able to adsorb radioactive elements strongly enough, resulting in low therapeutic efficacy against tumors. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, the technical problem to be solved by the present application is to solve the problem of the conventional yttrium [ 90 Y] microspheres, which has the drawback of insufficient adsorption strength, 90 Y] microspheres, their preparation method and use. [Means for solving the problem]

[0006] Therefore, the present application provides a yttrium [containing polystyrene sulfonate type resin microspheres and yttrium-90 adsorbed in the polystyrene sulfonate type resin microspheres. 90 Y] microspheres.

[0007] Furthermore, the polystyrene sulfonic acid type resin microspheres are prepared by reacting polystyrene microspheres with a sulfonating agent.

[0008] Furthermore, the sulfonating agent is one or more selected from liquid sulfur trioxide, concentrated sulfuric acid, chlorosulfonic acid, and sulfites, and preferably concentrated sulfuric acid.

[0009] In the present application, the concentrated sulfuric acid is 70% by mass or more, for example, 98% by mass.

[0010] Furthermore, the polystyrene microspheres can be obtained by mixing and reacting styrene as a monomer and divinylbenzene as a crosslinking agent with an aqueous solution containing a suspension aid in the presence of an initiator and a pore-forming agent.

[0011] Furthermore, the pore-forming agent is one or more selected from toluene and n-heptane, and / or the suspending aid is polyvinyl alcohol, and / or the initiator is benzoyl peroxide.

[0012] Furthermore, the method for preparing the polystyrene sulfonate resin microspheres includes: Preparation of polystyrene microspheres, which comprises mixing and dissolving styrene, divinylbenzene, an initiator, and a pore-forming agent to obtain an oil phase, pouring the oil phase into an aqueous solution containing a suspending aid, shear emulsifying the mixture, and heating the mixture to react to obtain polystyrene microspheres; and preparing polystyrene sulfonate type resin microspheres by adding polystyrene microspheres to concentrated sulfuric acid, dispersing them with ultrasonic waves, and reacting them by heating to prepare polystyrene sulfonate type resin microspheres.

[0013] Furthermore, in the preparation of polystyrene microspheres, the heating reaction temperature is 80-100°C and the time is 2-5 hours. Before the heating reaction, the mixture is stirred overnight at 40-60°C. The shear emulsification time is 3-10 minutes.

[0014] Furthermore, in the preparation of polystyrene sulfonate resin microspheres, polystyrene microspheres are added to concentrated sulfuric acid at 0°C to 4°C, and the temperature is raised to 37°C to 45°C to cause a reaction.

[0015] Furthermore, after the reaction at elevated temperature, the method further includes the steps of suction filtration, washing, drying, and sieving.

[0016] Furthermore, the polystyrene microspheres are prepared from the following raw materials: It is produced from 100 parts by volume of a polyvinyl alcohol-containing aqueous solution, 2.5 to 5.5 parts by volume of styrene, 1.2 to 4.2 parts by volume of divinylbenzene, 0.02 to 2.02 parts by weight of benzoyl peroxide, 0.6 to 1.6 parts by volume of toluene, and 0 to 1.6 parts by volume of n-heptane, The formulation relationship between parts by weight and parts by volume is g / mL.

[0017] Furthermore, the yttrium [ 90 Y] The radioactivity of the microspheres is 2.5–25 GBq / g.

[0018] Furthermore, the polyvinyl alcohol content in the polyvinyl alcohol-containing aqueous solution is 0.5 to 3% by mass (for example, 1%, 2%, or 0.8% by mass).

[0019] Furthermore, the particle size of the polystyrene sulfonic acid type resin microspheres is 10 to 60 μm, preferably 28 to 35 μm, and more preferably 30 to 35 μm.

[0020] This application also Yttrium chloride [ 90 Step S1 of mixing a yttrium-89 sulfate solution, a polystyrene sulfonate resin microsphere, Wash with buffered salt solution and water, and yttrium [ 90 and step S2 of obtaining yttrium [Y] microspheres. 90 Y] A method for preparing microspheres is provided.

[0021] Furthermore, the yttrium chloride [ 90 The ratio of the radioactivity of the Y] solution, the volume of the yttrium sulfate-89 solution, and the mass of the polystyrene sulfonate resin microspheres is 30-200 GBq: 30-200 ml: 5-15.5 g, and preferably the concentration of the yttrium sulfate-89 solution is 1-9.5 g / L.

[0022] Yttrium chloride [ 90 Y] solution concentration is 1-5 mg / mL.

[0023] Furthermore, the ratio of the volume of the buffer salt solution to the mass of the polystyrene sulfonate type resin microspheres is 70 to 300 mL:5 to 15.5 g.

[0024] Furthermore, the concentration of the buffer salt is 2 to 60 g / L.

[0025] Further, the buffer salt solution is one or more selected from sodium phosphate solution, sodium dihydrogen phosphate solution, disodium hydrogen phosphate solution, potassium phosphate solution, potassium dihydrogen phosphate solution, dipotassium hydrogen phosphate solution, PBS solution, sodium acetate, and Tris-HCl buffer solution, and optionally, in step S2, washing is first performed with the sodium phosphate solution and then with the sodium dihydrogen phosphate solution.

[0026] Furthermore, in step S2, the substrate is washed successively with water and a sodium phosphate solution, and then with a sodium dihydrogen phosphate solution and water.

[0027] Furthermore, the concentration of the sodium dihydrogen phosphate solution is 2 to 25 g / L, and the concentration of the sodium phosphate solution is 10 to 60 g / L.

[0028] The present invention also relates to a method for producing yttrium [ 90 Y] microspheres or yttrium [Y] prepared by any of the preparation methods described above 90 Y] microspheres, and further comprising a pharmaceutically acceptable auxiliary material, optionally wherein the pharmaceutically acceptable auxiliary material is selected from a solvent; 90 Y] microsphere pharmaceutical formulations are provided.

[0029] The solvent may be a common solvent such as distilled water, water for injection, or aqueous glucose solution. 90 In the pharmaceutical formulation of yttrium [Y] microspheres, the yttrium [ 90 Y] The radioactivity of the microspheres is 3–20 GBq.

[0030] Furthermore, the pharmaceutical preparation is an injection solution, and the radioactivity of the injection solution per unit dose is 3 to 20 GBq.

[0031] The yttrium [ 90 Y] Contains 0.8 to 4 g of microspheres.

[0032] In this application, yttrium [ 90 The preparation method of Y] microsphere injection may further include steps such as conventional intermediate radioactivity detection, filling, sterilization or product radioactivity detection.

[0033] At the time of filling, the volume filled per vial is 5 ml.

[0034] The present application also relates to a method for preparing a drug for preventing or treating liver cancer, comprising administering to a patient a compound containing yttrium [ 90 Y] microspheres or yttrium [prepared by any of the above-described preparation methods 90 Y] microspheres, or the use of any of the pharmaceutical formulations described above.

[0035] Raw material (yttrium chloride [ 90 The incoming raw material (yttrium chloride [Y] solution) is commercially available and its radioactivity can be set. According to the radioactivity meter operation manual, the radioactivity of the radioactive raw material at the time of production is adjusted to match the target radioactivity. 90 Measure and record the radioactivity of the desired radioactive material. The formula for calculating the radioactivity is A = kA / e -0.26t where k is the process loss coefficient, A0 is the radioactivity value at the calibration time, A is the radioactivity value at the measurement time, and t is the difference in days between the measurement time and the calibration time. [Effects of the Invention]

[0036] The technical solution of this application has the following advantages: 1. Yttrium according to the present application [ 90 The Y] microspheres comprise polystyrene sulfonic acid type resin microspheres and yttrium-90 adsorbed in the polystyrene sulfonic acid type resin microspheres. By adsorbing yttrium-90 on the polystyrene sulfonic acid type resin microspheres, the adsorption strength is significantly improved, the safety of preparation and use is significantly improved, and the killing effect on tumor cells is also favorable. 2. Yttrium according to the present application [ 90Y]microspheres, by adjusting the particle size of the polystyrene sulfonate type resin microspheres to 10 to 60 μm, particularly 28 to 43 μm, and most preferably 30 to 35 μm, the killing effect against liver cancer can be effectively improved. Microspheres with a particle diameter of 32.5 μm±2.5 μm have a density in water of 1.125 to 1.6 g / ml (equivalent to red blood cells) and can withstand moist heat sterilization. 3. Yttrium according to the present application 90 The microspheres contain 100 parts by volume of a polyvinyl alcohol-containing aqueous solution, 2.5 to 5.5 parts by volume of styrene, 1.2 to 4.2 parts by volume of divinylbenzene, 0.02 to 2.02 parts by weight of benzoyl peroxide, 0.6 to 1.6 parts by volume of toluene, and 0 to 1.6 parts by volume of n-heptane. By adjusting the blending ratio of each substance in the formulation within a preferred range, the resulting polystyrene sulfonate resin microspheres have a significantly improved ionic capacity. 4. Yttrium according to the present application 90 Y] microsphere injection solution is the yttrium [ 90 Y] microspheres, and by adsorbing yttrium-90 with polystyrene sulfonic acid type resin microspheres, the amount of precipitated yttrium ions is reduced, the safety of preparation and use is significantly improved, and the killing effect on tumor cells is also favorable. 5. Yttrium according to the present application 90 In step S2, the microsphere injection solution is first washed with sodium phosphate solution, and then the resin microspheres washed with sodium dihydrogen phosphate solution are firmly bonded with yttrium ions, resulting in less precipitated yttrium ions and significantly improved safety. DETAILED DESCRIPTION OF THE INVENTION

[0037] The following examples are provided for a better understanding of the present application, and are not limited to preferred embodiments, nor are they intended to limit the content and scope of protection of the present application. Any products identical or similar to those of the present application, which are suggested by the present application or obtained as a result of combining the features of the present application with other prior art, are intended to fall within the scope of protection of the present application.

[0038] Unless specific experimental steps or conditions are described in the examples, they are carried out according to the procedures or conditions of conventional experimental steps described in the literature in the field. Unless the manufacturers of the reagents or instruments used are specified, they are all ordinary reagent products that can be purchased on the market.

[0039] In the present application, the liquid can be discharged using a common commercially available filter, such as a filter manufactured by Merck Millipore or Steritech, USA, model number TKT04700 / PCT12047100, polycarbonate, filter pore size 10-18 μm, flow rate 15-65 ml / min.

[0040] yttrium[ 90 The preparation process of Y] microsphere injection solution includes the following steps:

[0041] Transfer of microspheres: Add water for injection to the polystyrene sulfonate-type resin microspheres to form a suspension of the microspheres, which is then transferred to a reaction vessel. Addition of yttrium solution: The yttrium sulfate-89 solution is added to the yttrium chloride [ 90 Y] solution was transferred to a transport vial containing yttrium chloride [ 90 Transfer the [Y] solution into a reaction vessel together with the yttrium-89 sulfate solution, stir to mix for at least 10 minutes (e.g., 10-50 minutes), and then drain the liquid with a filter. First washing of the microspheres with water: Add water for injection to the reaction vessel, stir to mix for at least 1 minute (e.g., 5 to 20 minutes), filter, and drain the liquid. Repeat this step one or more times. Buffer Salt Wash: Add buffer salt solution to the reaction vessel, stir to mix for at least 5 minutes, and filter to drain the liquid. Water washing: Inject 100 ml of water for injection into the reaction vessel, stir for at least 1 minute (e.g., 10 minutes) to mix, and then filter and drain the liquid. Repeat the steps to obtain yttrium [ 90 Y] microspheres, inject water for injection, filter and drain the liquid, adjust the volume of the solution in the reaction vessel to the desired volume, and add yttrium [ 90 Y] to obtain microsphere injection solution.

[0042] Example 1 This example provides a method for preparing polystyrene sulfonate resin microspheres, and the reagents used in the preparation are polyvinyl alcohol (PVA), styrene (St), divinylbenzene (DVB), toluene, n-heptane, ethanol, and benzoyl peroxide (BPO).

[0043] The preparation method is as follows. S1: First, St and DVB are each washed once with a 10% aqueous solution of sodium hydroxide, and then washed three times with water. S2: PVA was dissolved in water by heating to make 100 ml of a 1% (mass percentage) PVA aqueous solution, and the mixture was protected with nitrogen to obtain an aqueous phase. 2.5 ml of Stabilizer, 1.2 ml of DVB, 0.02 g of BPO, 0.6 ml of toluene, and 0.6 ml of n-heptane were weighed, mixed, and dissolved to obtain an oil phase. The oil phase was poured into the aqueous phase, and shear emulsification was performed using a shear machine for 5 minutes. The mixture was stirred at 50°C overnight, and then reacted at 90°C for 3 hours to obtain polystyrene microspheres. The mixture was suction filtered, washed twice with water, washed once with ethanol, and dried. S3: Dried polystyrene microspheres were added to 25 mL of concentrated sulfuric acid (98% by mass) at 0°C, then dispersed by ultrasonic treatment, heated to 40°C and reacted overnight. The mixture was filtered under suction, washed until neutral, slurried twice with hot water at 95°C, washed once with ethanol, and dried. S4: Polystyrene sulfonate resin microspheres with particle diameters of 30 to 35 μm were collected by sieving.

[0044] This example also contains yttrium [ 90 Y] microsphere injection and its preparation method are provided, and the prescription amount for 10 vials of injection is shown in Table 1 below.

[0045] [Table 1]

[0046] Preparation of yttrium-89 sulfate solution: Dissolve 0.3 g of yttrium-89 oxide powder in 80 ml of 0.1 M sulfuric acid at 40° C. to prepare yttrium-89 sulfate solution and place in a production storage container.

[0047] The preparation method is as follows. (1) Transfer of microspheres: 100 mL of water for injection was added to the polystyrene sulfonate type resin microspheres to form a suspension of the microspheres, and the entire suspension was transferred to a reaction vessel. (2) Addition of yttrium solution: Add yttrium sulfate-89 solution to yttrium chloride [ 90 Y] solution into the reaction vessel via a transport vial. 90 The [Y] solution was transferred to a reaction vessel along with the yttrium-89 sulfate solution, stirred for 10 minutes to mix, and the liquid was drained through a filter. (3) First washing of microspheres with water: 100 ml of water for injection was added to the reaction vessel, stirred for 1 minute to mix, filtered and the liquid was drained. This step was repeated twice. (4) Rinse the microspheres with phosphate: Add 120 ml of 30 g / L sodium phosphate solution to the reaction vessel, stir and mix for 10 minutes, filter and drain the liquid, add 150 ml of 10 g / L sodium dihydrogen phosphate solution, stir and mix for 5 minutes, filter and drain the liquid. (5) Second washing of the microspheres: 100 ml of water for injection was poured into the reaction vessel, stirred for 1 minute, filtered to remove the liquid, and rinsed twice. 100 ml of water for injection was poured into the reaction vessel, filtered to remove the liquid, and the volume of the solution in the reaction vessel was adjusted to 50 ml. (6) Filling: 5 mL of the solution was allocated to each vial, and the vials were stoppered and capped. This step was controlled by an automated system, meaning that filling, stoppering, and capping were performed automatically. (7) Sterilization: 132°C, 7 minutes.

[0048] According to the radioactivity measurement method (Chinese Pharmacopoeia 2020, Part 4 General Rule 1401), yttrium [ 90 The radioactivity measured for the Y]microsphere injection is 6 GBq / vial.

[0049] Example 2 This example provides a method for preparing polystyrene sulfonate-type resin microspheres, which is similar to the raw materials and process of Example 1, except that in step S4, after sieving, resin microspheres with a particle size of 28-33 μm are collected.

[0050] In this example, yttrium [ 90 Y] microsphere injection and its preparation method are provided, the raw materials and process are the same as those in Example 1, except that the polystyrene sulfonate type resin microspheres prepared in this example are used instead of the polystyrene sulfonate type resin microspheres in Example 1.

[0051] Example 3 This example provides a method for preparing polystyrene sulfonate-based resin microspheres, which is similar to the raw materials and process of Example 1, except that in step S4, after sieving, resin microspheres with a particle size of 38-43 μm are collected.

[0052] In this example, yttrium [ 90Y] microsphere injection and its preparation method are provided, the raw materials and process are the same as those in Example 1, except that the polystyrene sulfonate type resin microspheres prepared in this example are used instead of the polystyrene sulfonate type resin microspheres in Example 1.

[0053] Example 4 This example provides a method for preparing polystyrene sulfonate-type resin microspheres, which is similar to the raw materials and process of Example 1, except that in step S4, after sieving, resin microspheres with a particle size of 13-18 μm are collected.

[0054] In this example, yttrium [ 90 Y] microsphere injection and its preparation method are provided, the raw materials and process are the same as those in Example 1, except that the polystyrene sulfonate type resin microspheres prepared in this example are used instead of the polystyrene sulfonate type resin microspheres in Example 1.

[0055] Example 5 This example provides a method for preparing polystyrene sulfonate-type resin microspheres, which is similar to the raw materials and process of Example 1, except that in step S4, after sieving, resin microspheres with a particle size of 48-53 μm are collected.

[0056] In this example, yttrium [ 90 Y] microsphere injection and its preparation method are provided, the raw materials and process are the same as those in Example 1, except that the polystyrene sulfonate type resin microspheres prepared in this example are used instead of the polystyrene sulfonate type resin microspheres in Example 1.

[0057] Experimental Example 1 In the preparation of polystyrene sulfonate-based resin microspheres, the effects of various pore-forming agents, cross-linking agents, and their amounts on the ion exchange capacity of the polystyrene sulfonate-based resin microspheres were investigated. The preparation method was the same as in Example 1, except that the oil phase composition was different, as shown in the table below. The ion exchange capacity of polystyrene sulfonate-based resin microspheres prepared by the following methods A to C, as well as commercially available microspheres, was tested.

[0058] The specific method is as follows: An appropriate amount of polystyrene sulfonate resin microspheres was added to 100 ml of purified water, stirred for 1 minute, rinsed three times, and filtered. The filtered resin microspheres were weighed and designated M. The microspheres were immersed in 500 ml of 0.02 M sodium hydroxide solution and ultrasonicated for 20 minutes. After suction filtration, two drops of phenolphthalein were added to 100 ml of the filtrate, and a titration experiment was performed using 0.01 M hydrochloric acid. The volume of hydrochloric acid used until the titration endpoint was recorded and designated V. Formula for calculating ion exchange capacity: Ion exchange capacity (mmol / g) = (molarity of sodium hydroxide solution × volume of sodium hydroxide – molarity of hydrochloric acid × V) / M.

[0059] [Table 2]

[0060] [Table 3]

[0061] From the above table, it can be seen that the ion exchange capacity of the resin microspheres produced in groups A to C of the present application is significantly improved compared to commercially available products, and in particular, group A, which was produced by a method similar to that of Example 1, is significantly improved compared to both groups B and C.

[0062] Experimental Example 2: Treatment test of nude mice bearing primary hepatocellular carcinoma 1. Test Method 3 × 10 SMMC-7721 cells were injected into female nude mice weighing 20 g ± 2 g. 6 The animals were inoculated at a dose of 100 mg / animal. When tumor masses grew to 5-10 mm, they were randomly divided into experimental groups 1-5 and a control group (5 animals per group), and treatment began. 1 mL of each injection solution prepared in Examples 1-5 was diluted to a constant volume of 10 mL with water to obtain the test drug solution for each group. Each animal in experimental groups 1-5 was intraperitoneally injected with the test drug solution prepared in Examples 1-5 (5 mL / animal) once daily for 10 consecutive days. The control group received the same volume of water for injection and was observed for 10 days. After 10 days, administration was stopped. 24 hours after administration was stopped, all animals were sacrificed, tumor masses were excised, and tumor weights were measured. The tumor inhibition rate was calculated using the following formula: Tumor inhibition rate = (tumor weight of control group - tumor weight of experimental group / tumor weight of control group) × 100%

[0063] 2. Test Results [Table 4]

[0064] From the above table, it can be seen that the microspheres prepared in Examples 1 to 3 have a much better killing effect on tumor cells than those prepared in Examples 4 and 5. Example 1 is the best, and Example 2 is the second best.

[0065] Experimental Example 3 Each phosphate cleaning agent contains yttrium [ 90 The effect of the yttrium chloride [Y] microsphere encapsulation rate and the elution rate of the yttrium element was investigated. The type of phosphate in step (4) was different (in groups D and E, the added yttrium chloride [ 90 The same procedure as in Example 1 was used to prepare yttrium [Y] solution, except that the concentration of the solution was different. 90 Y] microsphere injection solution was prepared. For group A, the procedure was the same as in Example 1, that is, first washed with sodium phosphate solution, and then washed with sodium dihydrogen phosphate solution. The specific procedures for step (4) for group A and the remaining groups are shown in Table 5 below, and the other steps were the same as in Example 1.

[0066] Yttrium produced in each group [ 90 Y] All filtrates produced during the preparation of the microsphere injection solution (including all filtrates from the steps of adding yttrium solution, the first water washing step of the microspheres, rinsing the microspheres with phosphate, and the second water washing step of the microspheres) were collected and filtered through a 0.45 μm filter to obtain test product solution 1, and the concentration of yttrium ions in test product solution 1 was tested using an inductively coupled plasma mass spectrometer (referred to as yttrium ions in the filtrate).

[0067] Yttrium produced in each group [ 90 [Y] The microspheres were removed from the microsphere injection solution by filtration, and the collected storage solution was filtered through a 0.45 μm filter to obtain test product solution 2. The concentration of yttrium ions in test product solution 2 (precipitated yttrium ions) was tested using an inductively coupled plasma mass spectrometer.

[0068] Creating a calibration curve: Y 89 50 μL of the standard solution was measured into a 10 mL measuring flask and adjusted to the desired volume using 2% nitric acid to obtain a 5 mg / L intermediate solution. 0.02 mL, 0.1 mL, 0.2 mL, 0.4 mL, and 1.0 mL of the intermediate solution were transferred to separate 10 mL measuring flasks, and 20 μL of a 10 mg / L Ge internal standard was added. The solution was adjusted to the desired volume using 2% nitric acid to obtain a 5 mg / L intermediate solution. 89 Standard solutions with concentrations of 10 μg / L, 50 μg / L, 100 μg / L, 200 μg / L, and 500 μg / L were obtained. The standard solution, test solution 1, and test solution 2 were detected using inductively coupled plasma mass spectrometry (ICP-MS). Test conditions were: acquisition mode: KED, RF power: 1550.0 W, cooling gas flow rate: 14,000 L / min, nebulization gas flow rate: 1,0600 L / min, auxiliary gas flow rate: 0.8 L / min, collision gas flow rate: 4,340 ml / min. A calibration curve was created based on the test solution concentrations and detection results, and the concentrations of yttrium ions in test solution 1 and test solution 2 were calculated using the calibration curve.

[0069] [Table 5]

[0070] [Table 6]

[0071] In the first half of the experiment, the methods of Groups D and E were unable to adsorb many yttrium ions, resulting in a high yttrium ion concentration in the filtrate, which posed a high safety risk. Therefore, 5 mg / mL yttrium chloride [ 90 Y] solution, 2 mg / mL yttrium chloride [ 90 Y] solution and 3.5 mg / mL yttrium chloride [ 90 Y] solution, respectively, and yttrium [ 90 Y] microsphere injection solution was prepared. From the experimental results, the concentration of yttrium ions added (i.e., yttrium chloride [ 90 It was found that even when the concentration of yttrium ions in the filtrate and the precipitated yttrium ions in Group 2 were reduced, the concentration of yttrium ions in the filtrate and the precipitated yttrium ions in Group 2 were higher than those in the preferred embodiment Group A of the present application.

[0072] As can be seen from the table above, the amount of yttrium ion deposition obtained in the experiment of Group A was significantly reduced, and no yttrium ions were detected in the filtrate. The resin microspheres prepared in Example 1 of the present application were firmly bonded with yttrium ions, resulting in less yttrium ion deposition, suggesting significantly improved safety in preparation and use. On the other hand, the other microspheres were less bonded with yttrium ions, resulting in more yttrium ions in the filtrate.

[0073] Of course, the above examples are merely illustrative and do not limit the embodiments. Those skilled in the art can make other different changes or modifications based on the above description. It is not necessary and cannot be possible to cover all the embodiments here. Any obvious changes or modifications derived in this way still fall within the scope of protection of the present invention.

Claims

1. yttrium[ 90 Y] microspheres, A yttrium-containing microsphere comprising polystyrene sulfonic acid type resin microspheres and yttrium-90 adsorbed in the polystyrene sulfonic acid type resin microspheres. 90 Y] microspheres.

2. The yttrium [of claim 1], characterized in that the polystyrene sulfonate type resin microspheres are prepared by reacting polystyrene microspheres with a sulfonating agent. 90 Y] microspheres.

3. The sulfonating agent is one or more selected from the group consisting of liquid sulfur trioxide, concentrated sulfuric acid, chlorosulfonic acid, and sulfite. 90 Y] microspheres.

4. The polystyrene microspheres are obtained by mixing and reacting styrene as a monomer and divinylbenzene as a crosslinking agent with an aqueous solution containing a suspension aid in the presence of an initiator and a pore-forming agent. 90 Y] microspheres.

5. The method for preparing the polystyrene sulfonic acid type resin microspheres includes: Preparation of polystyrene microspheres, which comprises mixing and dissolving styrene, divinylbenzene, an initiator, and a pore-forming agent to obtain an oil phase, pouring the oil phase into an aqueous solution containing a suspending aid, shear emulsifying the mixture, and heating the mixture to react to obtain polystyrene microspheres; The method for producing polystyrene sulfonate-type resin microspheres according to claim 4, further comprising the steps of: adding polystyrene microspheres to concentrated sulfuric acid, dispersing the microspheres with ultrasonic waves, and reacting the microspheres by heating to prepare polystyrene sulfonate-type resin microspheres; 90 Y] microspheres.

6. The yttrium [0023] according to claim 4 or 5, characterized in that the pore-forming agent is one or more selected from toluene and n-heptane, and / or the suspending aid is polyvinyl alcohol, and / or the initiator is benzoyl peroxide. 90 Y] microspheres.

7. The polystyrene microspheres are produced from raw materials including 100 parts by volume of a polyvinyl alcohol-containing aqueous solution, 2.5 to 5.5 parts by volume of styrene, 1.2 to 4.2 parts by volume of divinylbenzene, 0.02 to 2.02 parts by weight of benzoyl peroxide, 0.6 to 1.6 parts by volume of toluene, and 0 to 1.6 parts by volume of n-heptane; The yttrium [of claim 6], characterized in that the blending relationship between weight parts and volume parts is g / mL. 90 Y] microspheres.

8. The yttrium [of claim 1] characterized in that the radioactivity is 2.5 to 25 GBq / g. 90 Y] microspheres.

9. The yttrium [ 90 Y] microspheres.

10. The yttrium [ 90 Y] microspheres.

11. The yttrium [ 90 Y] microspheres.

12. Yttrium chloride [ 90 Step S1 of mixing a yttrium-89 sulfate solution, a polystyrene sulfonate resin microsphere, and a yttrium-89 sulfate solution; After filtration, washing with a buffered salt solution and water was carried out to remove yttrium [ 90 and step S2 of obtaining yttrium [Y] microspheres according to any one of claims 1 to 11. 90 Y] Method for preparing microspheres.

13. The yttrium chloride [ 90 The ratio of the radioactivity of the yttrium-89 sulfate solution, the volume of the yttrium-89 sulfate solution, and the mass of the polystyrene sulfonate resin microspheres is 30 to 200 GBq: 30 to 200 ml: 5 to 15.5 g. 90 Y] Method for preparing microspheres.

14. The yttrium sulfate-89 solution according to claim 13, wherein the concentration of the solution is 1 to 9.5 g / L. 90 Y] Method for preparing microspheres.

15. The yttrium [of claim 12], characterized in that the ratio of the volume of the buffer salt solution to the mass of the polystyrene sulfonate type resin microspheres is 70 to 300 mL: 5 to 15.5 g. 90 Y] Method for preparing microspheres.

16. The yttrium [according to claim 12, characterized in that the buffer salt solution is one or more selected from sodium phosphate solution, sodium dihydrogen phosphate solution, disodium hydrogen phosphate solution, potassium phosphate solution, potassium dihydrogen phosphate solution, dipotassium hydrogen phosphate solution, PBS solution, sodium acetate, and Tris-HCl buffer solution. 90 Y] Method for preparing microspheres.

17. 17. The method of claim 16, wherein in step S2, the yttrium [ 90 Y] Method for preparing microspheres.

18. 13. The method according to claim 12, wherein in step S2, the yttrium [ 90 Y] Method for preparing microspheres.

19. The yttrium [of claim 18], characterized in that the concentration of the sodium dihydrogen phosphate solution is 2 to 25 g / L, and the concentration of the sodium phosphate solution is 10 to 60 g / L. 90 Y] Method for preparing microspheres.

20. The yttrium according to any one of claims 1 to 11 [ 90 Y] microspheres, or yttrium [ prepared by the preparation method according to any one of claims 12 to 19 90 Y] microspheres, further comprising a pharmaceutically acceptable auxiliary material. 90 Y] Pharmaceutical formulations of microspheres.

21. 21. The yttrium [of claim 20], wherein the pharmaceutically acceptable auxiliary material is selected from solvents. 90 Y] Pharmaceutical formulations of microspheres.

22. 21. The yttrium [ 90 Y] Pharmaceutical formulations of microspheres.

23. 12. The yttrium compound according to claim 1, wherein the yttrium compound is a hydroxybenzoate or a hydroxybenzoate. 90 Y] microspheres, yttrium [prepared by the method according to any one of claims 12 to 19] 90 Y] microspheres or the use of a pharmaceutical formulation according to any one of claims 20 to 22.

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